COPD is now one of the most commonly diagnosed comorbidities in HIV infected (HIV+) patients. The predominant phenotype of COPD in HIV+ patients is emphysema, which occurs more frequently than in uninfected (HIV-) patients, even when adjusted for smoking history. Radiographically, we have found that emphysema appears more severe and diffuse with greater lower lobe involvement than in HIV- patients. Whether the pathogenesis and clinical course of emphysema in the context of HIV infection are distinct from emphysema in HIV- individuals is not fully understood. However, chronic inflammation, immune activation and associated endothelial activation mediate other end-organ damage in HIV+ patients and are likely to be major contributors. Consistent with this, we found that elevated levels of soluble CD14 are associated with emphysema and decline in lung function in HIV+, but not in HIV- individuals. Our assessment of transcriptional signatures in peripheral blood leukocytes suggested perturbations in endothelial pathways in HIV+ patients with low lung diffusing capacity (DLCO) compared to HIV- patients with similar DLCO. Taken together, our preliminary findings suggest that pathways leading to a low DLCO and emphysema are distinct in HIV+ individuals. In this project, we will test the hypothesis that HIV+ patients with emphysema, compared to HIV- patients with emphysema, have a greater degree of pulmonary vascular dysfunction. We suspect that this will manifest as physiologic differences in the prevalence and phenotype of pulmonary vascular disease, and biologically, will be associated with and potentially explained by differences in biomarkers of endothelial activation and dysfunction. To test this hypothesis, we will evaluate differences in cardiopulmonary function and pulmonary vascular physiology using pulmonary function tests, chest CT scans, cardiac MRI and cardiopulmonary exercise testing in a cross-sectional study of 150 HIV+ and 150 HIV- current and former smokers. We will determine abnormalities in the cardiac, pulmonary vascular and ventilatory systems; their relationship to exercise capacity; and delineate whether the cause for exercise limitation differs by HIV. To determine biologic differences associated with emphysema by HIV status, we will conduct novel analyses of the bronchoalveolar lavage fluid proteome and circulating markers including microRNAs. Our aims are to: 1. Compare physiologic differences related to pulmonary vascular disease in HIV+ and HIV- patients, adjusting for the presence and severity of radiographic emphysema; 2. Determine whether alveolar and circulating biomarkers of endothelial activation and dysfunction are associated with emphysema in HIV+ compared to HIV- patients. Results of these studies will allow us to comprehensively characterize clinical and biological differences in emphysema in HIV+ compared to HIV- patients with a focus on the role of pulmonary vascular dysfunction. Understanding whether emphysema is distinct in the context of HIV infection is crucial to tailoring patient management; developing novel preventative and therapeutic targets; and improving patient outcomes.